What is ribose

Ribose or D-Ribose is a naturally occurring pentose monosaccharide present in all living cells including the blood and is an essential component for biological energy production 1). D-Ribose is also a product of dietary nucleic acid digestion 2). Ribose or D-Ribose is a key component of many important biomolecules including ribonucleic acid (RNA) 3), adenosine triphosphate (ATP) 4) and Riboflavin (vitamin B2) 5). Many foods, such as wheat bran, eggs, meat, cheese and yeast, contain reasonable high concentrations of ribonucleic acid (RNA) and Riboflavin (vitamin B2). The pentose phosphate pathway can convert hexose to D-Ribose. Besides food, D-Ribose is orally administered to improve athletic performance and the ability to exercise by boosting muscle energy as a readily available source of energy.

Footnote: Note the absence of the hydroxyl (-OH) group on the 2’ carbon in the deoxy-ribose sugar in DNA as compared with the ribose sugar in RNA.

D-Ribose is a popular dietary supplement for humans and horses because of its crucial role in cellular bioenergetics. It is also used to improve symptoms of diseases such as chronic fatigue syndrome, fibromyalgia 8) and coronary artery disease 9).

The available data indicate that in humans, D-Ribose is rapidly and nearly completely absorbed when administered at 200 mg/kg body weight per hour for 5 hours 10). In humans, at dose levels above 3 g (about 40 mg/kg body weight), absorption was faster than metabolism. Application of D-Ribose with meals decreases absorption. In the body, D-Ribose is converted mainly to glucose via the pentose phosphate pathway, rather than nucleic acid precursors, which then is further used in the metabolism/biosynthesis. Part of the ribose and its metabolites is excreted via the urine and the percentage increases with increasing dose.

Several human studies which were not designed to assess the safety of D-Ribose found the administration of single oral doses of 2–87 g D-Ribose consistently report transient decreases of glucose concentrations within 1–3 hours. The transient decrease of glucose concentration was not associated with clinical symptoms of hypoglycaemia, except for one case, where a low‐weight female experienced short‐term symptoms of hypoglycaemia after ingesting 10 g of ribose in the fasted state 11). While in this and in most of the other studies, blood glucose levels did not fall below 2.8 mmol/L, a temporary significant decline of blood glucose to 2.6 mmol/L was observed in one study following a single oral dose of 10 g D-Ribose 12). The decrease in blood glucose comes along with increases in insulin levels. The glucose‐lowering effect occurs also if meals rich in carbohydrate or fat are ingested before uptake of D-Ribose.

No studies have investigated intake of D-Ribose in infants, young children and adolescents. Whether young age may be of special concern with regard the glucose‐lowering effects of D-Ribose is not known. However, the European Food Safety Authority Panel considers that children could be particularly vulnerable to glucose‐lowering effects of d‐ribose 13).

The European Food Safety Authority notes that there is a lack of understanding of the mechanisms responsible for the short‐term decrease in blood glucose reported in the human studies, only limited data on the dose–response relationship between D-Ribose and blood glucose levels, and uncertainty about the risk of symptomatic hypoglycaemia conditions, especially in susceptible persons.

Because the decrease in glucose levels and/or the occurrence of transient symptomatic hypoglycaemia (as reported in one case) is considered adverse, based on the human studies, the lowest observed adverse effect level (LOAEL) would be at intakes of 10 g of D-Ribose. Concerning the human data, taking the above issues into account, the European Food Safety Authority concludes that 5 g per day, equivalent to 70 mg/kg body weight per day, would be the No Observed Adverse Effect Level (NOAEL) with respect to hypoglycaemia that can be considered applicable for adults. For children, the European Food Safety Authority acknowledges the lack of human data directly relevant for this population group.

Based on the No Observed Adverse Effect Level (NOAEL) of 3,600 mg/kg body weight per day derived from the subchronic toxicity study in rats, an acceptable level of intake would be up to 36 mg/kg body weight per day. This is half the NOAEL value identified in the human studies for adults with respect to hypoglycaemia. The European Food Safety Authority concludes that 36 mg/kg body weight per day would also take into account the potentially increased sensitivity of certain population groups to hypoglycaemia, including children.

The body weight therefore concludes that the D-Ribose is safe for the general population at intake levels up to 36 mg/kg body weight per day 14).

Fenstad et al. 15) found significantly higher levels of uric acid (which were, however, still in the normal range) following oral administration of 10 g D-Ribose when compared to the dose of 2 g at 30 and 60 min, no changes in serum uric acid concentrations were reported by Thompson et al. 16) following ingestion of 10 g d‐ribose and in the study of Gross et al. 17), during or after treatment with 27–89 g d‐ribose. Gastrointestinal symptoms were noted at single intakes of around 70 g 18).

The occurrence of gastrointestinal problems, short‐term hypoglycaemia and hyperuricemia in some of the studies presented and the lack of long‐term studies analyzing the effect of high doses of D-Ribose, does not allow determining the safety and tolerance of a long‐term intake of D-Ribose 19).

D-ribose health concerns

As a reducing monosaccharide, Ribose has the ability to react with proteins to produce glycated derivatives 20). Glycation with Ribose (ribosylation) gives rise to advanced glycation end products (AGEs) more rapidly than glycation with D-glucose which requires a relatively long time 21). Ribosylation (glycation with Ribose) rapidly induces alpha synuclein to form highly cytotoxic molten globules of advanced glycation end products. Alpha synuclein (α-Syn) is the main component of Lewy bodies which are associated with several neurodegenerative diseases such as Parkinson’s disease 22). D-Ribose, however, is also closely associated with many fundamental processes in cellular metabolism. Seuffer 23) has determined the concentration of D-ribose (0.01–0.1 mM) present in cerebrospinal fluid (CSF) in the brain. D-Ribose is used to synthesize nucleotides, nucleic acids, glycogen, and other important metabolic products. D-Ribose is also formed in the body from conversion of D-glucose via the pentose phosphate pathway. Thus, D-Ribose is present both intracellularly and extracellularly, and has opportunities to react with proteins and produce glycated derivatives. For this reason, glycation of Alpha synuclein protein with D-ribose needs to be investigated.

In vitro studies showed that D-Ribose induces protein misfolding rapidly leading to globular-like aggregations that are cytotoxic to neuronal cells 24). Intraperitoneal injection of D-Ribose for 30 days revealed high levels of glycated proteins and advanced glycation end products (AGEs) in the blood and brain of wild type mice. The mice also exhibited impairment of spatial learning and memory 25). More recently, D-Ribose was found to be increased in the urine of type 2 diabetic patients 26), suggesting that diabetic patients may be suffered from metabolic imbalance of not only D-Glucose but also D-Ribose 27).

Ribose intake from the diet

Ribose is reported to be present in meat in varying amounts, e.g. 1–524 mg/100 g beef meat 28) and 6.4–39.5 mg/100 g chicken meat 29), with these differences probably attributable not only to the origin of the meat but also to differences in sampling or analytical methods. Lilyblade and Peterson 30) reported that the content of ribose increases post‐mortem during storage of chicken meat. The cooking process is reported to reduce the quantity of free ribose as this is involved in Maillard reactions.

RNA and free nucleotides are reported to be degraded in the intestinal tract and free ribose may partially be released by the action of nucleosidases 31).

Due to the lack of data in the literature, the intake levels of d‐ribose from the diet are largely unknown.

Ribose inside the body production

Based on the estimated mean daily intake of carbohydrates in the UK, i.e. 252 and 198 g in men and women, respectively, 32) and assuming (i) that 2/3 of these would be composed of glucose, and (ii) that 2–9% of glucose is utilised via the pentose phosphate pathway 33), it is estimated that the daily endogenous production of d‐ribose through the pentose phosphate pathway ranges from approximately 3–15 g/day. Additional information on the extent of the daily endogenous production of d‐ribose in the literature is lacking. The information is insufficient to draw conclusions on the extent of the daily endogenous production of d‐ribose.

D-ribose dosage

Fibromyalgia and chronic fatigue syndrome patients were given 5 grams three times daily 34).

Based on the No Observed Adverse Effect Level (NOAEL) of 3,600 mg/kg body weight per day derived from the subchronic toxicity study in rats, an acceptable level of intake would be up to 36 mg/kg body weight per day. This is half the NOAEL value identified in the human studies for adults with respect to hypoglycaemia. The European Food Safety Authority concludes that 36 mg/kg body weight per day would also take into account the potentially increased sensitivity of certain population groups to hypoglycaemia, including children.

The body weight therefore concludes that the D-Ribose is safe for the general population at intake levels up to 36 mg/kg body weight per day 35).

A study Wu et al. 38) showed that feeding D-Ribose daily through gavage to mice for 6 months is correlated with cognitive impairment. Mice treated with D-Ribose (3.75 g/kg per day) exhibited learning and memory decline and anxiety-like behavior, accompanied by Aβ-like deposition and Tau hyperphosphorylation in their brain, especially the hippocampus. These features are Alzheimer’s disease-like, both with regards to pathology (abnormal modifications and aggregations of Tau protein and Aβ peptide) and pathophysiology (memory loss accompanied by anxiety-like behavior). This suggests that D-Ribose-gavaged mouse model may be useful to study age-related cognitive impairment 39) and diabetic encephalopathy, conditions in which Aβ deposition and Tau hyperphosphorylation are found 40).

The D-Ribose-induced high level of Aβ-like deposition in the hippocampus demonstrates that mice can develop Aβ-like deposits even though the APP gene sequence of mice differs from that of humans 41). Previously, other scientists employed mice in a methanol-gavage experiment and found that methanol can distinctly promote hyperphosphorylation of Tau, but not Aβ deposition 42). However, by oral administration of D-Ribose, Aβ-like deposition can be induced under the experimental conditions. Amyloid β deposit is clear and robust.

D-Ribose is significantly increased in the brain of D-Ribose-treated mice. However, it did not markedly increase advanced glycation end levels in the brain, serum, liver and kidney under the experimental conditions. However, intraperitoneal injection of similar concentrations of D-Ribose for 30 days, as described 43), resulted in advanced glycation end accumulation in the mouse blood and brain. Whether D-Ribose elevates levels of advanced glycation ends in mice or not depends on the mode of administration. Thus, impairment of cognitive ability by oral administration of D-Ribose is probably not related to brain advanced glycation end accumulation, but rather the abnormally high levels of Aβ-like deposition and Tau hyperphosphorylation in mouse brain.

To compare the effects between D-Ribose and D-Glucose, oral administration of D-Glucose did not affect cognition. Even though D-Glucose showed elevated pS396 levels in the hippocampus and AT8 reactivity in the cortex, the elevations were not clearly seen by immunohistochemical staining of sections using antibodies AT8, pS396, p214 and T181. D-Glucose was found to reduce the percentage of open arm entries of mice in the elevated plus-maze test. However, the D-Glucose-gavaged mice did not show an abnormal behavior in the open field test, indicating that D-Glucose-gavaged mice may not be anxious. Oral administration of D-Glucose did not cause high levels of Aβ-like deposits. In contrast, gavage of D-Ribose resulted not only in high levels of Aβ-like deposition and Tau phosphorylation in the hippocampus, but also in memory loss and anxiety-like behavior.

The long-term administration of D-Ribose did not cause any significant changes in the body weight compared to mice treated with D-Glucose. Fasting blood sugar levels and advanced glycation end levels did not differ between the groups. Except for memory loss and anxiety, both D-Ribose- and D-Glucose-gavaged mice did not show additional abnormal behavior such as motor dysfunction, reduced muscle strength and impaired co-ordination.

As described by Segal and colleagues 44), D-Ribose can cause insulin release and decrease blood D-Glucose. Our results are similar to their findings. Since mice were gavaged with the sugar, it needs more insulin to regulate it. The secreted insulin induced lower level of blood sugar 45).

In Alzheimer’s disease, memory disorder is known as the most important symptom. Behavioral and psychiatric symptoms like anxiety and depression may also follow the memory loss. In this study 46), D-Ribose-treated mice exhibit an anxious symptom in open field test and elevated plus maze. The anxiety-like effect of D-Ribose on mice should be further investigated. Forced swim test showed that the mice under D-Ribose treatment behave more immobile, which indicates the depression state. While tail suspension test did not show any difference in the immobility time. Administration of D-Glucose as a control did not show anxiety-like behavior and significant depression state. Take all those results, oral administration of D-Ribose induces not only memory impairment but also anxious behavior in mice 47).

Oral administration of D-Ribose to mice also causes impaired memory functions, Tau hyperphosphorylation and Aβ-like deposition 48). These data suggest that an imbalance of D-Ribose metabolism may play a role in diabetic encephalopathy 49).

In summary, oral administration of D-Ribose leads to the impairment of cognitive ability and anxious behavior in mice 50). Meanwhile, D-Ribose-gavaged mice suffer from both Aβ-like deposition and Tau hyperphosphorylation in their brain, especially in the hippocampus 51). These abnormal modifications and the pathological aggregation of these proteins are probably correlated with the memory loss and anxiety-like behavior after D-Ribose treatment 52).